The hypothalamic-pituitary-gonadal (HPG) axis mediates important aspects of social, emotional, cognitive, and appetitive behavior in human males. Compelling evidence now exists that HPG function declines with age: on average, testosterone (T) levels among men in their 70's are about half of what they were in young adulthood. The neuropsychiatric implications of this decline are not known. Furthermore, the use of exogenous T as a therapeutic agent in men with depression and dysthymia, or as a deterrent to the development of dementia has not been systematically studied. In this Mentored Patient-Oriented Clinical Scientist Development Award proposal, a multi-disciplinary program of training and research is outlined that will equip the candidate to investigate the role of the HPG axis in modulating CNS activity, including affective, appetitive, and cognitive functions; and the therapeutic use of exogenous T in dysthymia and major depression. Specifically, the candidate will use epidemiological samples and methodologies, as well as endocrinological clinical trials, to delineate the neuropsychiatric manifestations of reduced T level. Then, in psychiatric clinical trials with depressed men, the candidate will investigate whether exogenous T has beneficial effects compared to placebo. The didactic education of the candidate during this award will be provided by four mentors: Steven Roose (for training coordination, and medical-psychiatric and clinical trials expertise), Harold Sackeim (for psychobiological and neuropsychiatric expertise), Peter Snyder (for endocrinological expertise), and John McKinlay (for epidemiological expertise). In addition, collaborative relationships have been arranged with Drs. D.P. Devanand, Jean Endicott, Donald F. Klein, Rafael Lantigua, Mary Sano, Ridwan Shabsigh, Yaakov Stern, Roger Vaughan, and Kimberly Yonkers. From the training program of didactic work, and the conduct of this research plan under their supervision, the candidate will expand his capabilities in epidemiologic and clinical trials methodology, acquire new skills in psychometrics and neuropsychology, and most importantly, develop an expertise in clinical endocrinology which can be applied to ongoing and future patient-oriented neuropsychiatric investigations. The goal of this award is to promote the candidate's training, generate new insights into the role of the HPG axis in male neuropsychiatric health, develop hypotheses about the potential therapeutic role of exogenous T in mental illnesses, and finally, to provide the candidate with the continuity of support necessary to develop a program of funded psychoendocrine research.